The present invention relates to particulate carriers which are useful as drug carriers in a drug delivery system (DDS) and to pharmaceutical compositions containing the carriers.
In the field of DDS, the term xe2x80x9cdrug carriersxe2x80x9d is used to refer to carriers that deliver drugs to target organs or cells. When drug carriers are in the form of particles, they are called particulate carriers. Particulate carriers are classified into microcapsules, microspheres, nanoparticles, etc. according to their sizes, shapes, and functions. Materials for preparing particulate carriers include lipids, polymers, etc.
The terms xe2x80x9cmicrocapsulesxe2x80x9d and xe2x80x9cmicrospheresxe2x80x9d are usually used to refer to particles whose diameter is several micrometers. Microcapsules are generally considered to embrace a broader category than microspheres. Particles formed of a polymer from the surface to the core are often distinguished from microcapsules and are referred to as microspheres these days.
The term xe2x80x9cnanoparticlesxe2x80x9d has conventionally been used to refer to polymeric colloids prepared through emulsion polymerization, as the particles size is on the order of several nanometers. However, it has recently become common practice to collectively refer to particles composed of natural or synthetic polymers, even though prepared through methods other than emulsion polymerization, as nanoparticles so long as the particle diameter is on the order of several nanometers.
Nanoparticles as particulate carriers were first studied for use as carriers for targeting, for example, anti-cancer agents. In the early studies, the primary object of application was injection (L. Grislain et al., International Journal of Pharmaceutics, 15, 335 (1984)). Since the mid 1980""s, studies of nanoparticles as oral dosage forms have come to be reported.
When drugs are prepared as the form of nanoparticles and used as oral dosage forms, the following are considered goals to attain: improvement of drugs with poor absorptive characteristic.(P. Maincent et al., Journal of Pharmaceutical Sciences, 75, 955 (1986); C. Damge et al., International Journal of Pharmaceutics, 36, 121 (1987)), oral dosage forms of peptide drugs such as insulin (C. Damge et al., Diabetes, 37, 246 (1988); P. Couvreur and F. Puisieux, Advanced Drug Delivery Reviews, 10, 141 (1993)), oral delivery of vaccines antigen (J. H. Eldrige, Journal of Controlled Release, 11, 205 (1990); P. U. Jani et al., International Journal of Pharmaceutics, 86, 239 (1992)), and controlled release of drugs (B. Hubert et al., Pharmaceutical Research, 8, 734 (1991)).
Moreover, like the case of microcapsules, nanoparticles are sometimes used in an attempt to ensure stability of drugs in gastrointestinal tract (M. Rogues et al., Diabetes, 41, 451 (1992)) or to reduce irritation caused by strongly stimulative drugs on gastrointestinal mucosa (N. Ammoury et al., Pharmaceutical Research, 8, 101 (1991)).
Nanoparticles for pharmaceutical use are principally prepared by one of the two methods. The first method is a typical microcapsulation method, which is practiced through phase separation or solvent evaporation.
When this method is practiced, there are usually used hydrophobic polymers that have customarily been used as additives for pharmaceuticals, such as polylactic acid (A. M. Ray et al., Journal of Pharmaceutical Sciences, 83, 845 (1994)), cellulose derivatives (H. Ibrahim et al., International Journal of Pharmaceutics, 87, 239 (1992), or polyacrylate derivatives (E. Allemann et al., International Journal of Pharmaceutics, 87, 247 (1992)).
The other method for the preparation of nanoparticles makes use of emulsion polymerization (L. Vansnick et al., Pharmaceutical Research, 1, 36 (1985); N. Al Khouri Fallouh et al., International Journal of Pharmaceutics, 28, 125 (1986)). In this case, hydrophobic polyvinyl compounds such as polystyrene, polyacrylate, and polymethacrylate are considered to serve as the material of the nanoparticles. Polycyanoacrylates are used quite often, especially polyisobutyl cyanoacrylate, which is an adhesive for surgical operations.
Drug products are prepared by combining a drug with nanoparticles so as to carry the drug. Drugs to be carried are usually hydrophobic compounds, because the method for preparing nanoparticles is not suitable for hydrophilic compounds. Although there have been reported some examples in which hydrophilic compounds are transformed into nanoparticles, they are in effect limited to only compounds (e.g., peptides) that are insoluble in water at a certain pH (Yoshiaki KAWASHIMA, The 114th Conference of Japan Pharmaceutical Society, Lecture Abstracts Vol. 4, page 9, 1994, Tokyo).
Examples of studies in which the thus-prepared nanoparticle-drug complexes are used so as to improve absorption of poor absorptive drugs, to prepare oral dosage forms of peptide drugs, and to control the release of drugs include the following.
P. Maincent et al. prepared nanoparticles of vincamine, a poor absorptive hypotensive drug, through use of polyhexyl cyanoacrylate and studied absorption enhancement effect. However, the absorption rate of vincamine after transformation into nanoparticles was only 1.6 times that before transformation (Journal of Pharmaceutical Sciences, 75, 955 (1986)).
C. Damge attempted to prepare oral dosage forms of peptides by encapsulating insulin into nanoparticles through use of polyisobutyl cyanoacrylate. However, a slight decrease in blood glucose was observed only when nanoparticles containing a considerable amount of insulin were administered perorally, under fasting, to rats that had experimentally induced diabetes (Diabetes, 37, 246 (1988)).
Moreover, B. Hubert et al. studied controlled release of drugs using darodipine, a hypotensive drug. However, they were successful only in reducing initial release of the drug by encapsulating the drug into nanoparticles (Pharmaceutical Research, 8, 734 (1991)). There is no report that controlled release was acheived by nanoparticles.
As described above, there was no particulate carriers that have the sufficient oral absorption enhancement effect of drugs. Accordingly, the present invention is directed to a particulate carrier that has an excellent enhancement effect of drug absorption, and also to a pharmaceutical composition containing the carrier.
The present inventors conducted extensive studies, focusing on graft copolymers as drug carriers particularly the absorption enhancement of drugs administered orally. They found that graft copolymers having graft chains composed of polyvinylamine compound show an excellent oral absorption enhancement effect, and filed a pertinent patent application (Japanese Patent Application Laid-Open (kokai) No. 8-268916). After continued studies, they unexpectedly found that combinations of one or more species of graft copolymers having the graft chains composed of poly N-alkylacrylamide or poly N-alkylmethacrylamide shown below exhibit a remarkably superior oral absorption enhancement effect as compared to conventional graft copolymers, leading to completion of the present invention.
Accordingly, the present invention provides a particulate carrier including a graft copolymer (A) having structural units of the following formulae (1) and (2): 
wherein
Q1 is a hydrogen atom, a methyl group, or a cyano group, and
Q2 is a hydrogen atom, 
wherein
R1 is a hydrogen atom or a halogenomethyl group,
R2 is a C1-C10 alkyl group,
R3 is a hydrogen atom or a C1-C10 alkyl group, and
R4 is a C1-C10 alkyl group, provided that the carbon number in total of R3 and R4 is between 3 and 20 inclusive; 
wherein
Q3 is a hydrogen atom or a methyl group,
Q4 is a group having the following structure: 
wherein A1 is a C1-C10 alkylene group,
Q5 is an oxygen atom or xe2x80x94NHxe2x80x94,
Q6 is a C1-C10 alkylene group,
Q7 is an oxygen atom or a sulfur atom,
X1 is an oxygen atom or two hydrogen atoms,
each of R5, R7, and R8 is a hydrogen atom or a methyl group,
R6 is a C1-C10 alkyl group,
l is a number from 1 to 100, and
each of m and n is a number from 0 to 100.
The present invention also provides a particulate carrier composition containing a composition (graft copolymer composition) of the following components (a) and (b):
(a) the aforementioned graft copolymer (A); and
(b) one or more graft copolymers selected from the group consisting of the following graft copolymers (B-1) and (B-2):
(B-1) a graft copolymer having structural units of the following formulae (1) and (3): 
wherein
Q1 is a hydrogen atom, a methyl group, or a cyano group, and
Q2 is a hydrogen atom, 
wherein
R1 is a hydrogen atom or a halogenomethyl group,
R2 is a C1-C10 alkyl group,
R3 is a hydrogen atom or a C1-C10 alkyl group, and
R4 is a C1-C10 alkyl group, provided that the carbon number in total of R3 and R4 is between 3 and 20 inclusive; 
wherein
Q8 is a hydrogen atom or a methyl group,
Q9 is a group having the following structure: 
wherein A2 is a C1-C10 alkylene group,
Q10 is an oxygen atom or xe2x80x94NHxe2x80x94,
Q11 is a C1-C10 alkylene group,
Q12 is an oxygen atom or a sulfur atom,
X2 is an oxygen atom or two hydrogen atoms,
each of R9, and R10 is a hydrogen atom or a methyl group,
R11 is a C1-C10 alkyl group, and
p and q are independently numbers from 0 to 100 such that the sum p+q is equal to or more than 1;
(B-2) a graft copolymer having structural units of the following formulae (1) and (4): 
wherein
Q1 is a hydrogen atom, a methyl group, or a cyano group, and
Q2 is a hydrogen atom, 
wherein
R1 is a hydrogen atom or a halogenomethyl group,
R2 is a C1-C10 alkyl group,
R3 is a hydrogen atom or a C1-C10 alkyl group, and
R4 is a C1-C10 alkyl group, provided that the carbon number in total of R3 and R4 is between 3 and 20 inclusive; 
wherein
Q13 is a hydrogen atom or a methyl group,
Q14 is a group having the following structure: 
xe2x80x83wherein A3 is a C1-C10 alkylene group,
Q15 is an oxygen atom or xe2x80x94NHxe2x80x94,
Q16 is a C1-C10 alkylene group,
Q17 is an oxygen atom or a sulfur atom,
X3 is an oxygen atom or two hydrogen atoms,
each of R12 and R13 is a hydrogen atom or a methyl group,
R14 is a C2-C11alkanoyl group, and s and t are independently numbers from 0 to 100 such that the sum s+t is equal to or more than 1.
The present invention also provides a pharmaceutical composition containing a drug and the aforementioned graft copolymer (A), or a drug and the aforementioned graft copolymer composition containing the components (a) and (b).